The issue of cancer in the elderly is of growing concern given the aging population. It is a particular issue in lung cancer, where the median age of patients is over 60.
The issue of cancer in the elderly is of growing concern given the aging population. It is a particular issue in lung cancer, where the median age of patients is over 60. Aging is associated with changes in respiratory, cardiovascular, and hepatic physiology that are of particular importance to patients with thoracic disease in general and lung cancer in particular. In addition, the close association between tobacco abuse and lung cancer (90% of patients with lung cancer are current or ex-smokers) raises unique issues. As a result of tobacco abuse, the majority of lung cancer patients will be at elevated risk for cardiovascular and pulmonary diseases compared with other individuals of similar age. The issue of lung cancer treatment in the elderly has been the subject of recent comprehensive reviews.1
Elderly patients with lung cancer should neither be undertreated nor overtreated. In the past, arbitrary numerical definitions of age have resulted in undertreatment. This is particularly relevant in the area of curative therapy, where undertreatment can result in an elevated risk of recurrence. Those caring for patients with lung cancer should not lose sight of the fact that this is an extraordinarily symptomatic disease, and morbidity due to the local and systemic effects of the disease can be considerable. Conversely, overtreatment can also be a risk. Geriatric patients with lung cancer are clearly at greater risk for toxicity due to chemotherapy and other interventions, particularly if they are frail or have serious comorbidity. Judicious, individualized care based on the results of clinical research is critical for these patients.
The current staging system for non–small-cell lung cancer (NSCLC) is about to undergo significant change.2 The previous system (6th edition) was based on a relatively limited number of cases (approximately 6,000) from referral institutions in the United States and was driven by surgical issues. A proposed revision will incorporate data from > 60,000 patients and approach staging issues from all viewpoints (surgical, radiation, and medical). The comments below apply to both systems.
Lung cancer staging is broadly illustrated in Table 1. Stages I and II are localized disease that may be amenable to a potentially curative surgical resection in patients physiologically able to undergo such a procedure. Stage III is locally advanced disease; there are at least three major subsets: those with stage III defined by mediastinal nodal involvement, those defined by direct invasion of tumor into major structures (heart, vertebral body, major vessels), and those defined by malignant effusions. The latter group has now been incorporated into stage IV. Patients with stage III disease, defined by mediastinal nodal involvement or tumor invasion, can be considered for multimodality therapy with potentially curative intent. Stage IV disease is defined by distant metastatic disease. Patients with stage IV disease are primarily managed with chemotherapy (where appropriate) and also may benefit from radiotherapy and surgery in appropriate circumstances. Occasional stage IV patients with solitary metastases (particularly in the brain) may be cured with surgical resection or stereotactic radiotherapy.
Localized Disease (Stages I and II)
The management of elderly patients with stages I and II disease is similar to that of younger patients. Careful preoperative evaluation should be undertaken to exclude metastatic disease and to assure that any intervention is physiologically tolerable. As previously noted, compromised cardiovascular and pulmonary physiology is common in these patients. Preoperative assessment should be extensive, consisting of pulmonary function testing and cardiac stress testing. Positron emission tomography (PET) imaging is always indicated for both evaluation of the mediastinum as well as detection of occult metastatic disease. Though mediastinoscopy is controversial, I favor it for the majority of patients, even when the PET scan is normal. It is critical that mediastinoscopy sample all appropriate nodes, specifically 2R, 4R, 10R, 7 for right-sided lesions and 7, 10R, 10L for left lower-lobe lesions. Left upper-lobe lesions may require a Chamberlain procedure to sample level 5 nodes.3 Endobronchial ultrasonography (EBUS) is an emerging technology that is complementary to mediastinosopy and of particular use in assessing mediastinal tumor invasion.4
If physiologically possible, surgery is the preferred therapy for elderly patients with localized disease. Elderly patients may be cured, and the overall complication rate is comparable to that of younger patients undergoing thoracotomy for NSCLC.5 The SEER (Surveillance, Epidemiology, and End Results) database indicates that long-term survival decreases with age, though the reasons are unclear.6 Patients with borderline pulmonary function may be best served by resection performed with video-assisted thoracoscopic surgery (VATS).
In general, resection should be consistent with basic oncologic surgical principles; ie, non-anatomic resections (wedge resections) should be avoided, and at least segmentectomy or lobectomy should be performed. Segmentectomy is associated with a higher risk of local tumor recurrence.7 However, the SEER data indicate that for patients > 71 years of age, the value of lobectomy over segmentectomy or even wedge resection is unclear. This retrospective, population-based analysis found that survival was similar regardless of the surgical procedure. However, these findings should be viewed with caution, as the data analyzed are over 10−15 years old and it is unclear whether elderly patients underwent the same degree of staging as younger patients.6
For patients in whom resection is not possible, a growing body of literature indicates excellent results with stereotactic body radiotherapy (SBRT). SBRT has the potential to definitively treat small (< 3 cm) lesions located at least 2 cm from the mediastinum.8 Randomized trials should assess the role of SBRT relative to surgery in the "borderline" resectable patient.
Adjuvant chemotherapy has now become the accepted standard of care for patients with resected stages IIa, IIb, and IIIa disease.9−11 The absolute benefit in terms of survival is at least 5% and may be more than 10%. This finding is comparable (if not superior) to the level of benefit seen with adjuvant chemotherapy for breast or colon cancer. As in these diseases, this benefit in lung cancer must be weighed against the toxicity of therapy. A recent retrospective National Cancer Institute (NCI)−Canada study assessed adjuvant chemotherapy consisting of 4 cycles of cisplatin/vinorelbine versus observation in patients > 70 years of age. The investigators found a comparable level of benefit for elderly versus younger patients, albeit with greater toxicity.12 (A useful tool for evaluating the potential benefit of adjuvant chemotherapy that factors in age, stage, and comorbidity can be found at www.adjuvantonline.com.)
Locally Advanced Disease (Stage III)
The current standard of care for stages IIIa and selected IIIb disease is concurrent chemoradiotherapy.13 This approach has been shown to be superior to sequential chemotherapy and irradiation. The major drawback of this approach is the increased toxicity, particularly in the form of pneumonitis and esophagitis. Analysis of Radiation Therapy Oncology Group (RTOG) trials indicates that the elderly (ie, > 70 years) enjoy a comparable level of benefit, with somewhat increased toxicity.14 The North Central Cancer Treatment Group performed a similar subset analysis of a randomized trial and found no difference in terms of survival for patients < 70 or > 70 years of age.15 In contrast, a recent Cancer and Leukemia Group B (CALGB) study found a slight adverse effect for patients older than age 70 (hazard ratio = 1.018) compared with younger patients.16
The role of surgery in multimodality therapy remains controversial. The negative results of the intergroup study clearly demonstrate that surgery should not be routinely employed. However, retrospective analysis demonstrating a possible benefit in lobectomy patients and the unacceptably high incidence of death after pneumonectomy continues to raise questions about the role of surgery in all patients with lung cancer.17
Advanced Disease (Stages IIIb with Effusions and IV)
The most robust data regarding therapy in the elderly are in the advanced-disease setting (Table 2). Several randomized trials have demonstrated that single-agent chemotherapy is superior to so-called best supportive care. The ELVIS (Elderly Vinorelbine Italian Study) trial demonstrated superior survival and quality of life in older patients treated with chemotherapy.18 Studies with single-agent gemcitabine (Gemzar) have also demonstrated similar results. A comparison of docetaxel (Taxotere) as a single agent versus vinorelbine showed an advantage for docetaxel in terms of response, progression-free survival, and disease-related symptoms but only a trend toward improved overall survival.19
The role of combination chemotherapy is more controversial. A small trial comparing gemcitabine/vinorelbine with vinorelbine alone was halted because of superiority in the combination arm. However, a much larger and better analyzed trial demonstrated no advantage for gemcitabine/vinorelbine over either single agent alone.20 In either case, the regimen of gemcitabine/vinorelbine may not represent an optimal approach, as it was inferior to platinum-based chemotherapy in a randomized trial in a general population and is theoretically unattractive, as the agents demonstrate in vitro antagonism.
A more appropriate question centers on platinum-based therapy versus the single agent. Platinum-based combination chemotherapy represents the standard of care in the general lung cancer population.13 CALGB 9730 evaluated paclitaxel versus carboplatin/paclitaxel. The study found a numerically, but not statistically, significant superiority for combination chemotherapy. A predetermined subgroup analysis of elderly (> 70 years) patients found that there was a similar trend.21 The overall level of benefit was comparable between the elderly and younger patients. Interestingly, the greatest relative benefit of carboplatin was noted in those with a performance status (PS) of 2, implying that those with the most disease symptoms may obtain the greatest relative benefit.
Much of the controversy regarding the use of multiagent therapy in advanced disease emerges from the preliminary analysis of the Eastern Cooperative Oncology Group (ECOG) 1594 trial that evaluated four different platinum-based chemotherapy regimens. This study initially allowed patients with a PS of 2 to participate and ultimately found that these patients suffered serious morbidity and mortality. This study has frequently been interpreted to imply that platinum-based chemotherapy is not appropriate in the elderly. However, ECOG investigators determined that "fit" elderly patients did as well as other patients.22 Similarly, an analysis of a randomized phase III trial comparing three combination chemotherapy regimens (carboplatin/paclitaxel, carboplatin/gemcitabine, and gemcitabine/paclitaxel) found that the outcomes in terms of survival and toxicity were similar for older and younger patients.23
Of considerable interest is the role of the recently approved anti-VEGF (vascular endothelial growth factor) agent bevacizumab (Avastin). This agent was tested in combination with carboplatin and paclitaxel in a phase III trial (ECOG 4599). The population chosen was different from that of prior studies of advanced lung cancer; it excluded patients with squamous histology, recent thrombotic events, or therapeutic anticoagulation requirements. The study demonstrated a significant advantage for bevacizumab. Ramalingam and colleagues have performed a subgroup analysis of patients older than age 70 enrolled on the trial. These patients did not obtain a survival benefit, most likely as a result of significantly increased toxicity, primarily in the form of a greater risk of neutropenia, bleeding, proteinurea, muscle weakness, and motor neuropathy.24
The results in second-line chemotherapy are similar to the results in first-line chemotherapy in elderly patients, albeit with somewhat greater toxicity. A subgroup analysis of a randomized phase III trial of docetaxel versus pemetrexed (Alimta) demonstrated comparable results in older and younger patients.25
The duration of chemotherapy for any group of patients has been the subject of much debate. Clinical trials evaluating first-line platinum-based chemotherapy have demonstrated that 3−4 cycles of therapy provide the optimal degree of benefit, with little benefit obtained beyond 4 courses and marked cumulative toxicity. There are no data regarding the optimal duration of second- or third-line agents, nor regarding the actual benefit of bevacizumab in first-line therapy.26
Little information exists regarding octogenarians with lung cancer. A recent review of two multi-institutional trials demonstrates that selected patients in their 80s can obtain benefit from therapy in terms of disease control and survival with acceptable toxicity.27
Though a relatively small part of the total lung cancer burden (15%−20% of cases), small cell lung cancer (SCLC) is a major disease. The number of cases/year exceeds that of ovarian carcinoma and other major malignancies. Similar to those with NSCLC, typical patients with SCLC are older than age 60. There is a relatively limited literature regarding specific issues of therapy for SCLC in the elderly.
Treatment options under study for elderly patients with SCLC are listed in Table 3. The current standard of care, based upon a randomized phase III intergroup trial, is for patients with limited-stage SCLC to be treated with concurrent chemoradiotherapy followed by 2 additional cycles of chemotherapy.28 Radiation should be hyperfractionated (twice daily) to a total of 45 Gy, with chemotherapy consisting of cisplatin/etoposide. In addition, based upon a meta-analysis of randomized trials, there is a consensus that patients achieving a complete response or a "good" partial response should also receive prophylactic cranial irradiation (PCI).
Relatively little information exists about the applicability of these recommendations to those older than age 70. Retrospective analysis of the intergroup study indicates that this approach is of benefit in elderly patients, but at the expense of increased toxicity (myelosuppression and pneumonitis).29 Analysis of similar studies and case series also demonstrate that cure is possible in this setting, with results roughly comparable to those of younger patients.30,31 Despite these positive assessments of the value of concurrent therapy, patient selection should be considered in this as in all other clinical studies and analysis of therapy. Patients with severe comorbidities, compromised PS, and significant frailty were probably not treated as aggressively as other patients.
The standard approach for advanced disease is 4−6 cycles of chemotherapy. In the United States and Canada, the primary chemotherapeutic regimen employed consists of a platinum agent combined with etoposide. Other regimens, such as cyclophosphamide, doxorubicin, vincristine (CAV), are employed elsewhere. The regimen of cisplatin/irinotecan (Camptosar) is commonly utilized in Japan and has also been employed in the United States. Given the significant fluid load required to administer cisplatin, substitution of carboplatin is commonly used. For patients whose disease progresses after treatment with first-line therapy, topotecan (Hycamtin) has received approval by the US Food and Drug Administration for "sensitive relapse." PCI has recently been demonstrated to improve survival in patients who have had any degree of response to initial chemotherapy in extensive-stage SCLC.32,33
Given the rapidly fatal course of extensive-stage SCLC and the significant symptomatology of the disease, treatment is reasonable in all age groups, including the elderly. The substitution of carboplatin for cisplatin has been demonstrated to yield similar response, survival, and palliation in the elderly, in a randomized phase III trial in Japan.34
There is an absolute benefit of approximately 5% in terms of cure rate with PCI in patients with limited-stage SCLC and improved survival in patients with extensive-stage SCLC. In limited-stage SCLC, this improvement was present regardless of age.33,34 However, these results should be viewed with caution, as there are relatively few long-term data on the neurocognitive sequelae of this intervention. In extensive-stage SCLC, the study demonstrating the advantage of PCI did not require pre-study imaging of the CNS, a standard recommendation in North America. Hence, a fraction of the patients entered in this study likely had preexisting asymptomatic CNS metastases, and the recommendation for PCI can likely be extended to include those with asymptomatic CNS metastases who have responded to chemotherapy.
Another area where PCI may play a role is after definitive management of stage III NSCLC. The CNS is the sole site of relapse in as many as 20% of patients with stage III NSCLC after management with multimodality therapy (chemoradiotherapy, chemotherapy followed by surgery). PCI can reduce the risk of CNS relapse by approximately 75%.35 Interestingly, there did not appear to be a difference in terms of long-term neurocognitive deficits with and without PCI.
The treatment approach to lung cancer in the elderly should be similar to that of lung cancer in younger patients. As with younger patients, consideration of other factors such as comorbidities and PS is of paramount importance in determining appropriate therapeutic options in elderly patients. The elderly are more likely to suffer from significant comorbid conditions, and therefore a judicious approach to therapy, particularly chemotherapy, is indicated. Though there is an increasing body of literature regarding the management of lung cancer in the elderly, many of the conclusions are based upon patients who were entered onto clinical studies and may therefore represent a select group. In addition, even among that group, relatively few were octogenarians, and therefore application of these data to that demographic group is uncertain. Clinical trials focused on the elderly or planned subset analysis evaluating the elderly is needed to provide evidence-based guidelines for this growing population.
Continuing Medical Education InformationLung Cancer in the Elderly: Factors to Consider
Activity Release Date: November 1, 2007
Activity Expiration Date: November 1, 2008
About the Activity
This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. The series is geared to oncologists and addresses new treatments of cancer or modifications thereof.
This activity has been developed and approved under the direction of Beam Institute.
Activity Learning Objectives
After reading this article, participants should be able to:
(a) Identify age-related factors that can affect the decision to use chemotherapy for elderly patients with lung cancer.
(b) Describe the characteristics of the stages of non–small-cell lung cancer (NSCLC).
(c) Discuss the therapeutic options for elderly patients with localized and extensive NSCLC as well as small cell lung cancer.
(d) Briefly explore the potential role of prophylactic cranial irradiation in managing patients with lung cancer.
This activity targets physicians in the fields of oncology and hematology.
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The opinions and recommendations presented herein are those of the author(s) and do not necessarily reflect the views of the provider or producer.
Dr. Lichtman has no significant financial interest or other relationship with the manufacturers of any product or providers of any service mentioned in the article. Dr. Edelman is a paid consultant for and receives honoraria and research funding from Lilly Oncology; he is a paid consultant for and receives research funding from Bristol Myers Squibb; he also receives research funding from Aventis and developed the data and safety monitoring plan for Genentech.
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